Project Summary: The capacity to acquire, store and recall knowledge of the world through experience and use this knowledge to maximize reward and avoid danger is essential for survival. In humans, this ability is fundamental to our sense of self and is in large part what makes us who we are. The brain's memory systems are also vulnerable to diseases, such as such as Alzheimer's diseases, Schizophrenia, Attention Deficit Disorder, and Stroke, that affect millions of people. If we are to adequately treat memory disorders, then we first need to understand the neurobiological processes that underlie memory function. Yet, our current understanding of these processes comes mainly from experiments done in brain slices and anesthetized animals, leaving unknown the actual mechanisms of memory formation, storage and recall. However, sufficient technology now exists that allow researchers to probe the neural mechanisms of memory function in animals engaged in memory related tasks. This proposal describes a new combinatorial approach to identify neurons that participate in a specific memory and measure and manipulate the activity of those neurons, their dendrites and their synapses in real-time in behaving animals before, during and following memory formation and recall. The central innovation in my proposal is to establish an empirically well-supported unifying model of the neurobiology of memory formation and recall from the level of synapses and dendrites to large-scale ensembles of neurons that is based on data obtained from behaving animals. It will first allow me to test the long-standing hypothesis in behaving animals that persistent changes in synaptic strength, caused by specific activity patterns between presynaptic inputs and postsynaptic dendrites that occur during learning, store a memory of the experience within a subset of connected neurons. This will create a foundation from which to understand how other brain regions and circuits contribute to the formation of memories. For instance, local inhibitory circuitry, glial cells and neuromodulatory circuits that target the hippocampus shape neural activity, and their contribution to memory formation can be investigated using the approaches described here. Another long-term goal is to determine the mechanisms that allow memories to be retrieved during recall, and the processes involved in reconsolidation that are thought to alter memories following memory recall. In addition, we would like to understand how episodic memories become independent from the hippocampus over long periods. Together, the research proposed here will provide a new level of understanding of the neural processes underlying memory function.